1. Field of the Invention
The present invention relates to drugs, particularly agents for further improving excretory potency of the urinary bladder. The present invention further to relates to crystals and pharmaceutical compositions comprising the crystals of a tricyclic, condensed, heterocyclic compound which inhibit acetylcholinesterase and improve excretory potency of the urinary bladder.
2. Description of Related Art
Inferior uropathy is a general term for subjective or objective disorders in a process through accumulation of urine (urinary storage) till excretion (urination), which may be classified into urinary cumulative disorders (incontinence of urine, pollakiuria, etc.), dysuria (difficulty of urination, scalding, obstruction of urinary tract, etc.), and the like. Inferior uropathy in the aged, particularly dysuria, especially dysuria caused by prostatomegaly, becomes a great problem of public concern with the advance of a recent aging society, though inferior uropathy may also be found in the youth.
Urination is, under the control of the urination center, controlled by the peripheral nervous system involving a parasympathetic nerve such as the pelvic nerve, the sympathetic nerve such as the hypogastric nerve, and the somatic nerve such as the pudendal nerve, and it is suggested that a variety of neurotransmitters (e.g., acetylcholine, adrenaline, ATP, Substance P, neuropeptide Y, etc.) are involved in urination.
As agents for treatment of dysuria, particularly difficulty of urination, those for increasing contraction of the muscles of the urinary bladder (detrusor) or relaxing sphincter muscle of the urethra to reduce urethral resistance have been used. As the agents acting on the muscle of the urinary bladder to increase the contraction, for example, cholinergic agents such as bethanechol, acetylcholinesterase inhibitors such as distigmine, and the like have been used. Bethanechol however is incompatible with pregnant women, peptic ulcers, organic ileus, asthma, hyperthyroidism, etc., because it has adverse effects such as epiphora, sweating, gastro-intestinal disorders, stomachache, etc. No entirely satisfactory drugs have yet been found.
As the acetylcholinesterase inhibitors increasing contraction of the muscle of the urinary bladder, carbamate-type acetylcholinesterase inhibitors having a carbamate structure (—OCON—) in its molecule (e.g., distigmine, neostigmine, etc.) are known. These carbamate-type acetylcholinesterase inhibitors are known to express their inhibitory effect based on the carbamate structure which is characteristic of the molecule (Goodman & Gilman's The PHARMACOLOGICAL BASIS OF THERAPEUTICS, Ninth ed., McGraw-Hill, New York, p. 161-176). However, it is known that, for example, distigmine is insufficient in its clinical efficacy since it contracts the muscle of the urinary bladder with constriction of the muscle of the urethra to increase urethral resistance and consequently make the voiding flow rate worse. In addition, neostigmine has not been used in therapy because of the short duration of its action (Takamichi Hattori and Kosaku Yasuda, “Sinkeiinseiboukou-No-Sindan-To-Chiryou (Diagnosis and Therapy of Neurogenic Bladder)”, 2nd Ed., p. 105-106, p. 139, Igaku-Shoin Ltd. Tokyo).
On the other hand, a variety of amine compounds which have an acetylcholinesterase inhibiting effect and are different from carbamate-type inhibitors in their structure have been reported as follows.
(1) Compounds of the following formula:
wherein B represents an optionally substituted saturated or unsaturated 5- to 7-membered aza-heterocyclic group; A is a bond or alkylene or alkenylene optionally substituted with hydrocarbon residue, oxo or hydroxy;  indicates a single bond or double bond (where when A is a bond,  indicates a single bond); R2 and R3 each represent independently hydrogen or optionally substituted hydrocarbon residue (but they are not hydrogen concurrently) or they may be taken with the adjacent nitrogen atom to form a cyclic amino group; n is 0, 1 or 2; and p is 1 or 2;or salts thereof as described in EP-A-0 378 207.
Such compounds as described are exemplified by 3-[1-(phenylmethyl)piperidin-4-yl]-1-[4-(pyrrolidin-1-yl)phenyl]-1-propanone, 1-[4-(N,N-dimethylamino)phenyl]-3-[1-(phenylmethyl)piperidin-4-yl]-1-propanone, and the like.
(2) Compounds of the following formula:
wherein X represents R1—N< (R1 is hydrogen, optionally substituted hydrocarbon group or optionally substituted acyl), oxygen or sulfur; R2 represents hydrogen or optionally substituted hydrocarbon group; the ring A represents an optionally substituted benzene ring; k is an integer of 0-3; m indicates an is of 1-8; and n is an integer of 1-6;or salts thereof as described in Japanese Patent Unexamined Publication No. (hereinafter referred to as JP-A) 5-140149/1993.
Such compounds as described above are exemplified by 3-[1-(phenylmethyl)piperidin-4-yl]-1-(2,3-dihydro-1H-indol-5-yl)-1-propanone, 3-[1-(phenylmethyl)piperidin-4-yl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone, and the like.
(3) Compounds of the following formula:
wherein R1 represents hydrogen, optionally substituted hydrocarbon group or optionally substituted acyl; the ring A represents an optionally further substituted benzene ring; n is an integer of 1 to 10; R2, R3 and R4 are the same or different representing hydrogen or optionally substituted hydrocarbon group, or R3 and R4 may be taken with the adjacent nitrogen atom to form an optionally substituted heterocyclic group, and R2 may be different respectively according to repetition of n; k is an integer of 0 to 3; m is an integer of 1 to 8; provided that when k=0 and m=2, then n>1;or salts thereof as described in JP-A 6-166676/1994.
Such compounds as described above are exemplified by 3-[1-(phenylmethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-3-[4-(phenylmethyl)piperazin-1-yl]-1-propanone, 1-[2-(phenylmethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl]-3-[4-(phenylmethyl)piperazin-1-yl]-1-propanone, and the like.
(4) Compounds of the following formula:
wherein the ring A represents an optionally further substituted benzene ring; the ring B represents an optionally substituted non-aromatic heterocyclic ring containing the same or different, two or more hetero atoms; R1 represents hydrogen or optionally substituted to hydrocarbon group, which may be different according to a repetition of n; Y represents an optionally substituted amino or an optionally substituted nitrogen-containing saturated heterocycle; and n is an integer of 1 to 10; or salts thereof as described in JP-A 6-206875/1994.
Such compounds as described above are exemplified by 3-[1-(phenylmethyl)piperidin-4-yl]-1-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1-propanone and the like.
(5) JP-A 7-206854/1995 discloses the formula:
wherein Ar represents an optionally substituted tricyclic condensed benzene ring group condensed with at least one heterocycle; n is an integer of 2 to 10; R1 represents hydrogen or optionally substituted hydrocarbon group, which may be different according to a repetition of n; Y represents 4-piperidinyl, 1-piperadinyl or 4-benzyl-1-piperidinyl, each of which may have a substituent or substituents.
Such compounds as described above are exemplified by 8-[3-[1-(phenylmethyl)-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one, 1-(1,2,2a,3,4,5-hexahydrobenz[cd]indol-6-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone, and the like.
Also described in the Japanese Patent Kokai Publication is an amorphous substance of 8-[3-[1-[(3-fluorophenyl)methyl]-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one or a salt thereof, which possesses an action to inhibit acetylcholine esterase.
(6) Compounds of the following formula:
wherein Ar represents an optionally substituted tetracyclic condensed heterocyclic group; n is an integer of 1 to 10; R1 represents hydrogen or optionally substituted hydrocarbon group, which may be different according to a repetition of n; Y represents an amino or nitrogen-containing saturated heterocyclic group, each of which may have a substituent or substituents; or salts thereof as described in JP-A 7-309835/1995.
Such compounds as described above are exemplified by 3-[3-[1-(phenylmethyl)-4-piperidinyl]-1-oxopropyl]-7,11b, 12,13-tetrahydro-5H-isoindolo[2,1-b][2]benzazepin-7-one, 2-[1-oxo-3-[1-(phenyl methyl)-4-piperidinyl]-4,5,7a,8,9,10,11,11a-octahydro-6H-pyrido[3,2,1-jk]carbazol-6-one, and the like.
(7) Amine compounds described in WO 93/07140, PCT Japanese Patent Unexamined Publication No. (hereinafter referred to as PCT JP-A) 6-500794/1994, JP-A 4-234845/1992, JP-A 6-116237/1994, JP-A 7-109275/1995, WO 97/37992, JP-A 5-148228/1993, JP-A 5-194359/1993, JP-A 6-507387/1994, PCT JP-A 7-502272/1995, PCT JP-A 8-511515/1996, JP-A 6-41070/1994, JP-A 5-9188/1993, JP-A 5-279355/1993, JP-A 5-320160/1993, JP-A 6-41125/1994, JP-A 5-345772/1993, JP-A 7-502529/1995, JP-A 64-79151/1989, JP-A 62-234065/1987, JP-A 4-235161/1992, JP-A 4-21670/1992, JP-A 9-268176/1997, and so on.
(8) Amine compounds described in JP-A 2-167267/1990, JP-A 63-166881/1988, JP-A 2-96580/1990, JP-A 3-153667/1991, JP-A 61-148154/1986, Japanese Patent Examined Patent No. (hereinafter referred to as JP-B) 5-41141/1993, JP-A 63-284175/1988, JP-A 3-95161/1991, JP-A 3-220189/1991, JP-A 4-134083/1992, JP-A 4-66571/1992, PCT JP-A 11-500144/1999, PCT JP-A 10-511651/1998, JP-A 4-290872/1992, JP-A 2-231421/1990, JP-A 4-18071/1992, JP-A 4-159225/1992, JP-A 4-346975/1992, WO 99/11625, J. Am. Chem. Soc., 1991, 113, p. 4695-4696, J. Am. Chem. Soc., 1989, 111, p. 4116-4117, WO 97/11077, Heterocycles, 1977, 8, p. 277-282, J. Chem. Soc. (C), 1971, p. 1043-1047, and so on.
(9) Amine compounds described in fP-A 2-91052/1990, JP-A 3-95143/1991, JP-A 3-141244/1991, JP-A 3-223251/1991, JP-A 5-239024/1993, JP-A 2-138255/1990, and so on.
Moreover, amine compounds having various pharmacological actions have been reported as follows.
(1) WO 91/03243 describes compounds of the following formula:
wherein m is 0 to 3, n is 0 to 3, and m and n are not 0 at the same time; p is 0 to 3; X is O, S, SO, SO2, NR6, CR7R8CO or CHOH; R1, R3 and R7 each represent hydrogen, C1-5 alkyl, halogen, NR10R11, OR, COOH, C2-6 carbalkoxy, CN, Ar, C1-5 alkoxy or C1-5 alkylthio; R2, R4 and R8 each represent hydrogen, C1-5 alkyl, C2-6 carbalkoxy, CN, C1-5 alkoxy or Ar1; when X is O, S, SO, SO2 or NR6, then R1, R2, R3 and R4 are not C1-5 alkoxy, C1-5 alkylthio, NR10R11 or OH; R5 represents hydrogen, alkyl, halogen, OH or alkenyl; R6 represents hydrogen, C1-5 alkyl or Ar1; Ar and Ar1 each represent naphthyl, pyridyl, pyrimidyl, indolyl, quinolinyl, isoquinolinyl or phenyl, and these groups may be substituted by C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl containing 1 to 7 halogen atoms, SH, S(O)t-C1-3 alkyl (t is 1, 2 or 3), C2-6 dialkylamino, halogen, C1-3 alkylamino, NH2, CN, NO2, SO3H, tetrazole, COOH, C2-6 carboalkoxy, CONH2, SO2, NO2, COR9, CONR12R13, SO2NR12R13, Ar2, OAr2 or SAr2; Ar2 is naphthyl or phenyl, and these groups may be substituted by C1-3 alkyl, C1-3 haloalkyl containing 1 to 7 halogen atoms, C1-3 alkoxy, halogen or C1-3 alkylthio; R9, R10, R11, R12 and R13 each represent hydrogen, C1-5 alkyl or phenyl, R10 and R11 together may form a C3-6 alkylene chain, R12 and R13 together may form a C3-6 alkylene chain; a or b indicates a double bond or single bond, but they are not double bonded at the same time;or pharmacologically acceptable salts thereof which can be used as antipsychotics.
(2) IP-A 52-72829/1977 describes compounds of the following formula:
wherein R is hydrogen, alkyl containing 1 to 4 carbon atoms, or aralkyl of which the alkyl portion contains 1 or 2 carbon atoms; X is hydrogen or halogen, alkyl, alkoxy or alkylthio, each of which may contain 1 to 4 carbon atoms, trifluoromethyl, nitro, hydroxy or unsubstituted amino, or amino substituted by 1 or 2 alkyl groups or acyl or alkylsulfonyl; A is a group —CO— or —CH2—; and n is 0, 1 or 2;or salts thereof which can be used in treatment of diseases caused particularly by serotonergic dysfunction.
In these compounds, however, there is neither report, suggestion nor disclosure on their effect as prophylactics or therapeutic agents for dysuria (difficulty of urination) or on their effect as excretion improving agents for urinary bladder.
Therefore, it has been a desire to develop prophylactics or therapeutic agents for dysuria, particularly difficulty in urination, which have a high efficiency for urination and high versatility compared with known compounds known to have an effect in improving excretion of the urinary bladder.
There has also been a desire in the pharmaceutical industry to attain crystals that are good in absorbability and are used for an acetylcholine esterase inhibitor, an agent for improving the excretory potency of a urinary bladder, and a therapeutic agent against micturition disorders/dysuria disorders which are stable.